Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder characterized by hamartomatous neurological lesions that exhibit abnormal cell proliferation and differentiation. Hyperactivation of ...mTOR pathway by mutations in either the
Tsc1 or
Tsc2 gene underlies TSC pathogenesis, but involvement of specific neural cell populations in the formation of TSC-associated neurological lesions remains unclear. We deleted
Tsc1 in
Emx1-expressing embryonic telencephalic neural stem cells (NSCs) and found that mutant mice faithfully recapitulated TSC neuropathological lesions, such as cortical lamination defects and subependymal nodules (SENs). These alterations were caused by enhanced generation of SVZ neural progeny, followed by their premature differentiation and impaired maturation during both embryonic and postnatal development. Notably, mTORC1-dependent Akt inhibition and STAT3 activation were involved in the reduced self-renewal and earlier neuronal and astroglial differentiation of mutant NSCs. Thus, finely tuned mTOR activation in embryonic NSCs may be critical to prevent development of TSC-associated brain lesions.
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Tsc1 deletion in eNSCs deregulates their self-renewal and differentiation ► mTOR hyperactivation in eNSCs disarranges postnatal neurogenesis in the SVZ and SGZ ► mTOR-dependent Akt inhibition impairs eNSC self-renewal in vitro ► Premature differentiation of eNSCs in vitro requires mTOR-dependent STAT3 activation
Epidermal growth factor receptor (EGFR) is a known diagnostic and, although controversial, prognostic marker of human glioblastoma multiforme (GBM). However, its functional role and biological ...significance in GBM remain elusive. Here, we show that multiple GBM cell subpopulations could be purified from the specimens of patients with GBM and from cancer stem cell (CSC) lines based on the expression of EGFR and of other putative CSC markers. All these subpopulations are molecularly and functionally distinct, are tumorigenic, and need to express EGFR to promote experimental tumorigenesis. Among them, EGFR-expressing tumor-initiating cells (TIC) display the most malignant functional and molecular phenotype. Accordingly, modulation of EGFR expression by gain-of-function and loss-of-function strategies in GBM CSC lines enhances and reduces their tumorigenic ability, respectively, suggesting that EGFR plays a fundamental role in gliomagenesis. These findings open up the possibility of new therapeutically relevant scenarios, as the presence of functionally heterogeneous EGFR(pos) and EGFR(neg) TIC subpopulations within the same tumor might affect clinical response to treatment.
Molecular and cellular changes are intrinsic to aging and age-related diseases. Prior cross-sectional studies have investigated the combined effects of age and genetics on gene expression and ...alternative splicing; however, there has been no long-term, longitudinal characterization of these molecular changes, especially in older age.
We perform RNA sequencing in whole blood from the same individuals at ages 70 and 80 to quantify how gene expression, alternative splicing, and their genetic regulation are altered during this 10-year period of advanced aging at a population and individual level. We observe that individuals are more similar to their own expression profiles later in life than profiles of other individuals their own age. We identify 1291 and 294 genes differentially expressed and alternatively spliced with age, as well as 529 genes with outlying individual trajectories. Further, we observe a strong correlation of genetic effects on expression and splicing between the two ages, with a small subset of tested genes showing a reduction in genetic associations with expression and splicing in older age.
These findings demonstrate that, although the transcriptome and its genetic regulation is mostly stable late in life, a small subset of genes is dynamic and is characterized by a reduction in genetic regulation, most likely due to increasing environmental variance with age.
Achaete-scute homolog 1 gene (ASCL1) is a gene classifier for the proneural (PN) transcriptional subgroup of glioblastoma (GBM) that has a relevant role in the neuronal-like differentiation of GBM ...cancer stem cells (CSCs) through the activation of a PN gene signature. Besides prototypical ASCL1 PN target genes, the molecular effectors mediating ASCL1 function in regulating GBM differentiation and, most relevantly, subgroup specification are currently unknown. Here we report that ASCL1 not only promotes the acquisition of a PN phenotype in CSCs by inducing a glial-to-neuronal lineage switch but also concomitantly represses mesenchymal (MES) features by directly downregulating the expression of N-Myc downstream-regulated gene 1 (NDRG1), which we propose as a novel gene classifier of MES GBMs. Increasing the expression of ASCL1 in PN CSCs results in suppression of self-renewal, promotion of differentiation and, most significantly, decrease in tumorigenesis, which is also reproduced by NDRG1 silencing. Conversely, both abrogation of ASCL1 expression in PN CSCs and enforcement of NDRG1 expression in either PN or MES CSCs induce proneural-to-mesenchymal transition (PMT) and enhanced mesenchymal features. Surprisingly, ASCL1 overexpression in MES CSCs increases malignant features and gives rise to a neuroendocrine-like secretory phenotype. Altogether, our results propose that the fine interplay between ASCL1 and its target NDRG1 might serve as potential subgroup-specific targetable vulnerability in GBM; enhancing ASCL1 expression in PN GBMs might reduce tumorigenesis, whereas repressing NDRG1 expression might be actionable to hamper the malignancy of GBM belonging to the MES subgroup.
Gene co-expression network analysis enables identification of biologically meaningful clusters of co-regulated genes (modules) in an unsupervised manner. We present here the largest study conducted ...thus far of co-expression networks in white blood cells (WBC) based on RNA-seq data from 624 individuals. We identify 41 modules, 13 of them related to specific immune-related functions and cell types (e.g. neutrophils, B and T cells, NK cells, and plasmacytoid dendritic cells); we highlight biologically relevant lncRNAs for each annotated module of co-expressed genes. We further characterize with unprecedented resolution the modules in T cell sub-types, through the availability of 95 immune phenotypes obtained by flow cytometry in the same individuals. This study provides novel insights into the transcriptional architecture of human leukocytes, showing how network analysis can advance our understanding of coding and non-coding gene interactions in immune system cells.
Idiopathic pulmonary fibrosis (IPF) is a complex disease in which a multitude of proteins and networks are disrupted. Interrogation of the transcriptome through RNA sequencing (RNA-Seq) enables the ...determination of genes whose differential expression is most significant in IPF, as well as the detection of alternative splicing events which are not easily observed with traditional microarray experiments. We sequenced messenger RNA from 8 IPF lung samples and 7 healthy controls on an Illumina HiSeq 2000, and found evidence for substantial differential gene expression and differential splicing. 873 genes were differentially expressed in IPF (FDR<5%), and 440 unique genes had significant differential splicing events in at least one exonic region (FDR<5%). We used qPCR to validate the differential exon usage in the second and third most significant exonic regions, in the genes COL6A3 (RNA-Seq adjusted pval = 7.18e-10) and POSTN (RNA-Seq adjusted pval = 2.06e-09), which encode the extracellular matrix proteins collagen alpha-3(VI) and periostin. The increased gene-level expression of periostin has been associated with IPF and its clinical progression, but its differential splicing has not been studied in the context of this disease. Our results suggest that alternative splicing of these and other genes may be involved in the pathogenesis of IPF. We have developed an interactive web application which allows users to explore the results of our RNA-Seq experiment, as well as those of two previously published microarray experiments, and we hope that this will serve as a resource for future investigations of gene regulation in IPF.
Hemoglobin switching is a complex biological process not yet fully elucidated. The mechanism regulating the suppression of fetal hemoglobin (HbF) expression is of particular interest because of the ...positive impact of HbF on the course of diseases such as β-thalassemia and sickle cell disease, hereditary hemoglobin disorders that affect the health of countless individuals worldwide. Several transcription factors have been implicated in the control of HbF, of which BCL11A has emerged as a major player in HbF silencing. SOX6 has also been implicated in silencing HbF and is critical to the silencing of the mouse embryonic hemoglobins. BCL11A and SOX6 are co-expressed and physically interact in the erythroid compartment during differentiation. In this study, we observe that BCL11A knockout leads to post-transcriptional downregulation of SOX6 through activation of microRNA (miR)-365-3p. Downregulating SOX6 by transient ectopic expression of miR-365-3p or gene editing activates embryonic and fetal β-like globin gene expression in erythroid cells. The synchronized expression of BCL11A and SOX6 is crucial for hemoglobin switching. In this study, we identified a BCL11A/miR-365-3p/SOX6 evolutionarily conserved pathway, providing insights into the regulation of the embryonic and fetal globin genes suggesting new targets for treating β-hemoglobinopathies.
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Maria Serafina Ristaldi and colleagues describe the discovery of an evolutionarily conserved BCL11A/microRNA-365-3p/SOX6 pathway involved in the suppression of embryonic and fetal β-like globin genes. Their findings could lead to the development of new therapeutic strategies for β-thalassemia and sickle cell disease (SCD), genetic disorders that affect millions of individuals worldwide.
A modern classic, Gramsci’s Prison Notebooks represents today a point of reference in diverse fields, from anthropolo-gy to history, from political theory to literary studies and so-ciology. In order ...to understand how Gramsci’s methodology functions, one needs to focus on movements between ‘high’ and ‘low’, aristocratic and popular, war of strategy and war of position, dominant and subaltern. Gramsci rediscovers young Marx’s revolutionary writings and adopts a radical stance in which Marxism coincides with an immanent – that is, mo-bile – critique of humanity in which institutions and common sense are stripped of any metaphysical residuals. Grams-ci called it philosophy of praxis and singled out philology as its instrument. This contribution aims at reconstructing the context in which this highly dynamic, anti-dogmatic concep-tion develops, eschewing determinism and the hidden teleol-ogy of positivism. Mobility as a theory of social change looms large in the Prison Notebooks, whereas passive revolution reflects the fixity of state centrism related to uneven social conditions. But above all the philosophy of praxis’ strength consists in its self-reflective faculty, what Said defines as “Traveling theory”, ideas and theories that move from one culture to another, involving processes of representation and institutionalization different from those of the point of origin, thus spreading critical consciousness through movement.
Joseph Buttigieg's A Portrait of the Artist in Different Perspective aims at providing a critical reconsideration of Joyce's work. Focusing on A Portrait of the Artist as a Young Man, it contributes ...to a radical revision of the central tenets of modernism as first established by T.S. Eliot's conservative reading in the 1920s and reiterated by the New Critics in the 1950s. Buttigieg's critical effort seeks to prevent Joyce's work from being locked up in a literary museum, drawing on a dialectical and highly perceptive ability to unmask Western metaphysics and aesthetics as ideologies within which conservative criticism had framed Joyce's Bildungsroman. Furthermore, his Maltese, English, Catholic roots made Buttigieg capable of identifying and demystifying high modernism's irony and disinterestedness as instruments of the "higher" values on which the entire Irish social system was based. Together with Seamus Deane and Declan Kiberd, Buttigieg was among the very first critics who realized the relevance of Portrait as an Irish national indictment against colonization because - as Deane maintains- it is the first novel to examine the distorted relationship between the Irish community and oppression and to focus on this oppression's ultimate resource - cooperation with the oppressed. This Joycean experience informed Buttigieg's study of Gramsci's method and its application in various fields of the social sciences, a heritage that has influenced scholarship throughout the world.
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